Tryptase, the predominant protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) N. Eng. J. Med. 316:1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific antigen challenge (Castells et al. (1988) J. Allerg. Clin. Immunol. 141:563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase levels, a finding that provides some support for the hypothesis that release of proteinase from activated mast cells could contribute to lung destruction in smoker""s emphysema. (Celenteron et al. (1988) Chest 94:119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. Clin. Invest. 88:493-499).
Asthma is recognized as an inflammatory disorder (Hood et al. (1984) In: Benjamin-Cummings, ed. Immunology 2nd ed.) and frequently is characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic stages. The hyper-responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall.
Allergic responses to inhaled allergens can initiate the inflammatory sequence. For example, allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release a number of preformed or primary chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation (e.g., superoxide, lipid derived mediators, etc.) in situ. In addition, several large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast cells.
The release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens. The early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site by release of mast cell derived chemotactic agents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes.
Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988) J. Pharmacol. Exp. Ther. 248:947-951; and Tam et al. (1990) Am. J. Respir. Cell Mol. Biol. 3:27-32) and modulation of bronchial responsiveness to histamine (Sekizawa et al. (1989) J. Clin. Invest. 83:175-179). These findings suggest that tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tryptase cleaves fibrinogen xcex1-chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, administration of tryptase inhibitor protects against development of the late and airway hyper-responsive phases in allergen challenged sheep (Clark et al. (1995) Am. J. Respir. Crit. Care Med. 152: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79(6):1966-1970). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic agents in treating asthma and other disorders associated with inflammation of the respiratory tract.
The disclosures of these and other documents, including patents and patent applications, referred to throughout this application are incorporated herein by reference.
This application relates to a compound of Formula I: 
in which:
n1 is 0 or 1,
n2 is 0, 1, 2, 3 or 4;
n3 is 0, 1, 2, 3 or 4;
A together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X1 and X2 are adjacent annular members of an aromatic ring and X1 is a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NR5xe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94, wherein R5 is hydrogen, (C1-6)alkyl or hetero(C2-6)alkyl;
C comprises a fused heteropolycyclic radical containing 8 to 18 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X4 and X5 are adjacent annular members of an aromatic ring, X5 is a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NR5xe2x80x94, and xe2x80x94Sxe2x80x94, wherein R6 is hydrogen, a group selected from (C1-8)alkyl or hetero(C2-12)alkyl, which group optionally is substituted with one to two substituents independently selected from (C1-6)alkanoyloxy, (C1-6)alkylamino, di(C1-6)alkylamino, tri(C1-6)alkylammonio, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, (C1-6)alkyloxy, (C1-6)alkyloxycarbonyl, (C1-6)alkyloxysulfonyl, amino, carboxy, carbamoyl, (C6-14)aryl, halo, hetero(C5-14)aryl, hydroxy and sulfo, or as defined below; and any carbocyclic ketone, thioketone and iminoketone derivative thereof;
X3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR7xe2x80x94 or xe2x80x94CR7R8xe2x80x94, wherein R7 is hydrogen, (C1-6)alkyl, hetero(C2-12)alkyl or together with R6 forms (C24)alkylene or hetero(C2-4)alkylene and R8 is hydrogen, (C1-6)alkyl or hydroxy or together with R7 forms (C2-6)alkylene or (C1-6)alkylidene, wherein any aliphatic or alicyclic moiety comprising R7 and/or R8 optionally are substituted with one to three substituents selected from (C1-6)alkylamino, di(C1-6)alkylamino, tri(C1-6)alkylammonio, (C1-6)alkyloxy, (C1-6)alkyloxycarbonyl, (C1-6)alkanoyloxy, amino, carboxy, carbamoyl, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, halo and hydroxy;
R1 is amino(N14)azolidinyl, amino(N1-4)azolyl, (N1-4)azolidinyl, (N1-4)azolyl, carbamoyl, cyano, xe2x80x94(CH2)xNHC(NR9)R9, xe2x80x94(CH2)xNHC(NH)NR9R9, xe2x80x94(NR9)R9, xe2x80x94C(NH)NHR10, xe2x80x94C(NH)NR10R10 or xe2x80x94(CR11R11)yNH2 and bonded to any annular atom with an available valence comprising B, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R9 independently is hydrogen or (C1-6)alkyl, each R10 is independently (C1-6)alkyl and each R11 independently is hydrogen, (C1-3)alkyl or together with another R11 and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R1 optionally is substituted with one to two substituents independently selected from (C1-6)alkyloxycarbonyl, (C1-6)alkanoyloxy, carboxy, carbamoyl, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, (C1-6)alkylsulfonyl and hydroxy;
each R2 independently is (C1-6)alkyl, (C1-6)alkyloxycarbonyl, (C1-6)alkanoyloxy, (C1-6)alkyloxy, carboxy, carbamoyl, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, (C1-6)alkylsulfinyl, (C1-6)alkylsulfonyl, (C1-6)alkylthio, halo or hydroxy and bonded to any annular atom with an available valence comprising B, wherein any aliphatic moiety comprising R2 optionally is substituted with one to two substituents independently selected from (C1-6)alkyloxycarbonyl, (C1-6)alkanoyloxy, carboxy, carbamoyl, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, (C1-6)alkylsulfonyl and hydroxy;
each R3 independently is (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)alkylthio, cyano, halo, perhalo(C1-6)alkyl or hydroxy and bonded to any annular atom with an available valence comprising C; and
R4 is xe2x80x94R12, xe2x80x94OR12, xe2x80x94N(R13)R12, xe2x80x94SR12, xe2x80x94S(O)R12, xe2x80x94S(O)2R12, xe2x80x94S(O)2OR12, xe2x80x94S(O)2N(R13)R12, xe2x80x94N(R13)S(O)2R12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94C(O)N(R13)R12, xe2x80x94N(R13)C(O)R12, xe2x80x94OC(O)N(R13)R12, xe2x80x94N(R13)C(O)OR12, xe2x80x94CH2)zN(R13)C(O)N(R13)R12, xe2x80x94OP(O)(OR13)O R12 or xe2x80x94C(O)N(R14)CH(COOH)R12 and bonded to any annular carbon atom with an available valence comprising C, wherein:
z is 0, 1 or 2,
R12 is xe2x80x94R15 or xe2x80x94X6xe2x80x94R15)n15, wherein n15 is 1 or 2, X6 is (C1-10)alkylene, cyclo(C3-10)alkylene, hetero(C2-10)alkylene or heterocyclo(C3-10)alkylene and each R15 is independently hydrogen, (C6-14)aryl, cyclo(C3-14)alkyl, polycyclo(C6-14)aryl, heteropolycyclo(C6-14)aryl, heterocyclo(C3-14)alkyl, hetero(C5-14)aryl or as defined below,
R13 is hydrogen, (C1-6)alkyl or hetero(C2-6)alkyl;
R14 is hydrogen, (C1-6)alkyl or together with X6 and R15 forms (C3-4)alkylene;
any aliphatic and alicyclic moiety comprising R4 optionally is substituted with one to five substituents independently selected from (C1-6)alkyl, (C1-6)alkylamino, di(C1-6)alkylamino, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, (C1-6)alkyloxy, (C1-6)alkyloxycarbonyl, (C1-6)alkylsulfinyl, (C1-6)alkylsulfonyl, (C1-6)alkythio, amino, (C6-10)arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and
any aromatic moiety comprising R15 optionally is substituted with one to three substituents independently selected from cyano, guanidino, halo, halo-substituted (C1-8)alkyl, xe2x80x94R16, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)2R16,xe2x80x94S(O)2R16,xe2x80x94S(O)2N(R13)R16xe2x80x94, xe2x80x94C(O)R16, xe2x80x94C(O)OR16 and xe2x80x94C(O)N(R3)R16, wherein R13 is as defined above and R16 is hydrogen, optionally mono-substituted (C1-8)alkyl (wherein the optional substitutent is (C1-6)alkylamino, di(C1-6)alkylamino, tri(C1-6)alkylammonio, (C1-6)alkylcarbamoyl, di(C1-6)alkylcarbamoyl, (C1-6)alkyloxycarbonyl, (C1-6)alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo(C3-6)alkyl, hetero(C1-8)alkyl, hetero(C1-6)aryl, heterocyclo(C3-6)alkyl or phenyl;
with the proviso that n1 is not 0, when n2 is 0 or R2 is (C1-6)alkyl or (C1-6)alkyloxy, n3 is 0 or R3 is (C1-6)alkyl or (C1-6)alkyloxy and R4 is hydrogen, (C1-10)alkyl or (C1-10)alkyloxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
The present invention also provides for pharmaceutical compositions of the compounds of the invention. These pharmaceutical compositions can be in a variety of forms including oral dosage forms, inhalable forms, as well as injectable and infusible solutions. When used in inhalant or aerosol form, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier solution or dry powder which can be converted into aerosol form. Similarly, when used in oral administration, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used for the treatment of immunomediated inflammatory skin conditions, the compounds of the present invention are used in combination with a non-toxic, pharmaceutically acceptable topical carrier. The compounds of the present invention can be used in combination with antiinflammatories or other asthma therapies, such as xcex2-adrenergic agonists, antiinflammatory corticosteroids, anticholinergics, bronchodilators such as methyl xanthenes and the like.
The compounds described herein are useful for the prevention and treatment of immunomediated inflammatory disorders, and particularly those associated with the respiratory tract, including asthma, and particularly the hyper-responsiveness phase associated with chronic asthma, and allergic rhinitis. Thus, the present invention also provides a method for treating immunomediated inflammatory disorders wherein a patient having an immunomediated inflammatory disorder is administered a therapeutically effective dose or amount of a compound of the present invention. Further, the compounds described herein are useful for treating syncytial viral infections.